Submissions for variant NM_000535.7(PMS2):c.1253C>T (p.Ser418Phe)

gnomAD frequency: 0.00001  dbSNP: rs587782640

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132033	SCV000187092	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-07	criteria provided, single submitter	clinical testing	The p.S418F variant (also known as c.1253C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1253. The serine at codon 418 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported in a lung cancer patient from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun. 2015 Dec 22;6:10086). This variant was also identified by multigene panel testing in an Italian individual who was diagnosed with invasive breast cancer at age 39; her family history did not meet Amsterdam criteria (Germani A et al. J Clin Med, 2020 Sep;9:). This alteration has also been reported in an individual, from a family meeting Amsterdam criteria, with colon cancer diagnosed at age 49 that was MSI-H and MLH1/PMS2 deficient on IHC, and the patient's brother who was also affected with colon cancer (Liccardo R et al. Int J Mol Med, 2022 Jun;49:). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000204928	SCV000260259	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 418 of the PMS2 protein (p.Ser418Phe). This variant is present in population databases (rs587782640, gnomAD 0.002%). This missense change has been observed in individual(s) with colon or lung cancer (PMID: 26689913, 35475445). ClinVar contains an entry for this variant (Variation ID: 142680). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PMS2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000656946	SCV000565397	uncertain significance	not provided	2023-04-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26689913, 34445161, 35475445, 32957588)
Genetic Services Laboratory, University of Chicago	RCV000485028	SCV000596469	uncertain significance	not specified	2016-11-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132033	SCV000686112	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 418 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with lung adenocarcinoma (PMID: 26689913) and one individual affected with breast cancer (PMID: 32957588). This variant has been identified in 2/251182 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656946	SCV004218947	uncertain significance	not provided	2022-09-28	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/251182 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with lung adenocarcinoma (PMID: 26689913 (2015)). In a large-scale breast cancer association study, the variant was observed one healthy control (PMID: 33471991 (2021), see also LOVD ( http://databases.lovd.nl/shared/genes/PMS2)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003998131	SCV004844247	uncertain significance	Lynch syndrome	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 418 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with lung adenocarcinoma (PMID: 26689913) and one individual affected with breast cancer (PMID: 32957588). This variant has been identified in 2/251182 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.